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NM_002880.4(RAF1):c.769T>A (p.Ser257Thr) AND RASopathy

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 24, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001869023.5

Allele description [Variation Report for NM_002880.4(RAF1):c.769T>A (p.Ser257Thr)]

NM_002880.4(RAF1):c.769T>A (p.Ser257Thr)

Gene:
RAF1:Raf-1 proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.2
Genomic location:
Preferred name:
NM_002880.4(RAF1):c.769T>A (p.Ser257Thr)
HGVS:
  • NC_000003.12:g.12604201A>T
  • NG_007467.1:g.64979T>A
  • NM_001354689.3:c.769T>A
  • NM_001354690.3:c.769T>A
  • NM_001354691.3:c.526T>A
  • NM_001354692.3:c.526T>A
  • NM_001354693.3:c.670T>A
  • NM_001354694.3:c.526T>A
  • NM_001354695.3:c.427T>A
  • NM_002880.4:c.769T>AMANE SELECT
  • NP_001341618.1:p.Ser257Thr
  • NP_001341619.1:p.Ser257Thr
  • NP_001341620.1:p.Ser176Thr
  • NP_001341621.1:p.Ser176Thr
  • NP_001341622.1:p.Ser224Thr
  • NP_001341623.1:p.Ser176Thr
  • NP_001341624.1:p.Ser143Thr
  • NP_002871.1:p.Ser257Thr
  • NP_002871.1:p.Ser257Thr
  • LRG_413t1:c.769T>A
  • LRG_413t2:c.769T>A
  • LRG_413:g.64979T>A
  • LRG_413p1:p.Ser257Thr
  • LRG_413p2:p.Ser257Thr
  • NC_000003.11:g.12645700A>T
  • NM_002880.3:c.769T>A
  • NR_148940.3:n.1100T>A
  • NR_148941.3:n.1100T>A
  • NR_148942.3:n.1100T>A
Protein change:
S143T
Links:
dbSNP: rs727505017
NCBI 1000 Genomes Browser:
rs727505017
Molecular consequence:
  • NM_001354689.3:c.769T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.3:c.769T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.3:c.526T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.3:c.526T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.3:c.670T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.3:c.526T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.3:c.427T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.4:c.769T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.3:n.1100T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.3:n.1100T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.3:n.1100T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
RASopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: C5555857

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002248201Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Apr 24, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germline gain-of-function mutations in RAF1 cause Noonan syndrome.

Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R.

Nat Genet. 2007 Aug;39(8):1013-7. Epub 2007 Jul 1.

PubMed [citation]
PMID:
17603482

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.

Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, et al.

Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1.

PubMed [citation]
PMID:
17603483
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV002248201.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser257 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603482, 17603483, 20052757, 22389993, 23877478). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 618340). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 257 of the RAF1 protein (p.Ser257Thr).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 5, 2024